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KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas

Antje Brockschmidt, Detlef Trost, Heike Peterziel, Katrin Zimmermann, Marion Ehrler, Henriette Grassmann, Philipp-Niclas Pfenning, Anke Waha, Dirk Wohlleber, Felix F. Brockschmidt, Manfred Jugold, Alexander Hoischen, Claudia Kalla, Andreas Waha, Gerald Seifert, Percy A. Knolle, Eicke Latz, Volkmar H. Hans, Wolfgang Wick, Alexander Pfeifer, Peter Angel, Ruthild G. Weber
DOI: http://dx.doi.org/10.1093/brain/aws045 1027-1041 First published online: 16 March 2012

Summary

In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name ‘focadhesin’. Since KIAA1797 genetic variation has been implicated in Alzheimer’s disease, our data are also relevant for neurodegeneration.

  • tumour relevant gene
  • functional characterization
  • focal adhesion complex
  • cell motility
  • glioma
  • Abbreviations
    array-CGH
    array-based comparative genomic hybridization
    BAC
    bacterial artificial chromosome
    CDKN2A
    cyclin-dependent kinase inhibitor 2A
    CDKN2B
    cyclin-dependent kinase inhibitor 2B
    CMV
    cytomegalovirus
    FISH
    fluorescence in situ hybridization
    GFP
    green fluorescent protein
    PCR
    polymerase chain reaction
    PGK
    phosphoglycerate kinase
    RT
    reverse transcriptase
    VASP
    vasodilator-stimulated phosphoprotein
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